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【结 构 式】 
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【分子编号】28637 【品名】Ethyl 2-[4-(benzyloxy)phenyl]acetate; p-(Benzyloxy)phenylacetate 【CA登记号】 |
【 分 子 式 】C17H18O3 【 分 子 量 】270.32812 【元素组成】C 75.53% H 6.71% O 17.76% |
合成路线1
该中间体在本合成路线中的序号：(III)The condensation of ethyl p-hydroxyphenylacetate (I) with benzyl chloride (II) by means of sodium ethoxide in refluxing ethanol gives ethyl p-(benzyloxy)phenylacetate (III), which is reduced with LiAlH4 in THF to 2-(p-benzyloxyphenyl)ethanol (IV). The etherification of (IV) with cyclopropyl bromide (A) by means of NaH in hot DMF affords 4-(cyclopropylmethoxyethyl)-1-benzyloxybenzene (V), which is debenzylated by hydrogenation with H2 and Pd/C in methanol giving rise to p-(cyclopropylmethoxyethyl)phenol (VI). The condensation of (VI) with epichlorohydrin (B) by means of NaOH in water yields 1-[p-(cyclopropylmethoxyethyl)phenoxy]-2,3-epoxypropane (VII), which is treated with isopropylamine (C) and finally with HCl in ether.
| 【1】 Manoury, P.M.J.; et al. (Sanofi-Synthelabo ); Phenol ethers. DE 2649605; FR 2330383; GB 1515978; JP 52085146; US 4252984 . |
| 【2】 Hillier, K.; Castaner, J.; Serradell, M.N.; Blancafort, P.; Betaxolol hydrochloride. Drugs Fut 1979, 4, 12, 867. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (B) | 10146 | Epichlorohydrin; 2-(Chloromethyl)oxirane | 106-89-8 | C3H5ClO | 详情 | 详情 |
| (A) | 22277 | Cyclopropyl bromide; 1-(Bromomethyl)cyclopropane | 7051-34-5 | C4H7Br | 详情 | 详情 |
| (I) | 24994 | Ethyl 2-(4-hydroxyphenyl)acetate | 17138-28-2 | C10H12O3 | 详情 | 详情 |
| (II) | 19171 | 1-(Chloromethyl)benzene; Benzyl chloride | 100-44-7 | C7H7Cl | 详情 | 详情 |
| (III) | 28637 | Ethyl 2-[4-(benzyloxy)phenyl]acetate; p-(Benzyloxy)phenylacetate | C17H18O3 | 详情 | 详情 | |
| (IV) | 33328 | 2-(p-Benzyloxyphenyl)ethanol; 2-[4-(Benzyloxy)phenyl]-1-ethanol | C15H16O2 | 详情 | 详情 | |
| (V) | 33329 | 4-(Cyclopropylmethoxyethyl)-1-benzyloxybenzene; 1-(Benzyloxy)-4-[2-(cyclopropylmethoxy)ethyl]benzene; Benzyl 4-[2-(cyclopropylmethoxy)ethyl]phenyl ether | C19H22O2 | 详情 | 详情 | |
| (VI) | 33330 | 4-[2-(Cyclopropylmethoxy)ethyl]phenol; p-(Cyclopropylmethoxyethyl)phenol | C12H16O2 | 详情 | 详情 | |
| (VII) | 33331 | 2-([4-[2-(Cyclopropylmethoxy)ethyl]phenoxy]methyl)oxirane; 1-[p-(Cyclopropylmethoxyethyl)phenoxy]-2,3-epoxypropane; 4-[2-(Cyclopropylmethoxy)ethyl]phenyl 2-oxiranylmethyl ether | C15H20O3 | 详情 | 详情 | |
| (C) | 23933 | 2-Propanamine; Isopropylamine | 75-31-0 | C3H9N | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(IV)The reaction of 7-hydroxy-1,2,3,4-tetrahydroisoquinoline (I) with di-tert-butyl dicarbonate and triethylamine in dichloromethane gives 7-hydroxy-1,2,3,4-tetrahydroisoquinoline-2-carboxylic acid tert-butyl ester (II), which is condensed with 2-(4-benzyloxyphenyl)-2-chloroacetic acid ethyl ester (III) (obtained by chlorination of 2-(4-benzyloxyphenyl)acetic acid ethyl ester (IV) with PCl5), by means of K2CO3 in refluxing acetonitrile yields the disubstituted acetate (V). The selective debenzylation of (V) with H2 over Pd/C in ethyl acetate affords the phenol (VI), which is alkylated with 4-hydroxypiperidine-1-carboxylic acid tert-butyl ester (VII) by means of diethyl azodicarboxylate (AZE) and triphenyl phosphine providing the protected intermediate (VIII). The deprotection of (VIII) with HCl in ethanol gives intermediate (IX) with two free NH groups, which is treated with pyrazole-1-carboxamidine (X) and diisopropylethylamine (DIEA) in DMF yielding the bis amidino derivative (XI), which is finally hydrolyzed with NaOH in ethanol/water.
| 【1】 Kucznierz, R.; Von der Saal, W.; Leinert, H.; Grams, F.; Stegmeier, K. (Roche Diagnostics GmbH); New cyclic guanidines, process for preparing the same and medicaments. DE 19530996; EP 0846115; JP 1999511445; WO 9708165 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (I) | 28634 | 1,2,3,4-tetrahydro-7-isoquinolinol | C9H11NO | 详情 | 详情 | |
| (II) | 28635 | tert-butyl 7-hydroxy-3,4-dihydro-2(1H)-isoquinolinecarboxylate | C14H19NO3 | 详情 | 详情 | |
| (III) | 28636 | ethyl 2-[4-(benzyloxy)phenyl]-2-chloroacetate | C17H17ClO3 | 详情 | 详情 | |
| (IV) | 28637 | Ethyl 2-[4-(benzyloxy)phenyl]acetate; p-(Benzyloxy)phenylacetate | C17H18O3 | 详情 | 详情 | |
| (V) | 28638 | tert-butyl 7-[1-[4-(benzyloxy)phenyl]-2-ethoxy-2-oxoethoxy]-3,4-dihydro-2(1H)-isoquinolinecarboxylate | C31H35NO6 | 详情 | 详情 | |
| (VI) | 28639 | tert-butyl 7-[2-ethoxy-1-(4-hydroxyphenyl)-2-oxoethoxy]-3,4-dihydro-2(1H)-isoquinolinecarboxylate | C24H29NO6 | 详情 | 详情 | |
| (VII) | 18625 | tert-butyl 4-hydroxy-1-piperidinecarboxylate | C10H19NO3 | 详情 | 详情 | |
| (VIII) | 28640 | tert-butyl 7-[1-(4-[[1-(tert-butoxycarbonyl)-4-piperidinyl]oxy]phenyl)-2-ethoxy-2-oxoethoxy]-3,4-dihydro-2(1H)-isoquinolinecarboxylate | C34H46N2O8 | 详情 | 详情 | |
| (IX) | 28641 | ethyl 2-[4-(4-piperidinyloxy)phenyl]-2-(1,2,3,4-tetrahydro-7-isoquinolinyloxy)acetate | C24H30N2O4 | 详情 | 详情 | |
| (X) | 15983 | 1H-pyrazole-1-carboximidamide | 4023-00-1 | C4H6N4 | 详情 | 详情 |
| (XI) | 28642 | ethyl 2-[4-([1-[amino(imino)methyl]-4-piperidinyl]oxy)phenyl]-2-([2-[amino(imino)methyl]-1,2,3,4-tetrahydro-7-isoquinolinyl]oxy)acetate | C26H34N6O4 | 详情 | 详情 |